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Summary of the impact

Researchers at the Mahidol-Oxford Research Unit (MORU) in Thailand
performed the first comparative trials to unambiguously show artemisinin
resistance in Plasmodium falciparum parasites in western Cambodia,
as well as its emergence on the Thailand-Myanmar border. These studies
emphasised the importance of urgent containment, leading to rapid
responses from the World Health Organization (WHO) and international
governments for the tracking and containment of drug-resistant malaria.

Underpinning research

The Plasmodium falciparum parasite is transmitted by the female
Anopheles mosquito and causes the most dangerous form of malaria in
humans. Due to vital research from the University of Oxford's
Mahidol-Oxford Research Unit (MORU) in Thailand, ACT was recommended by
the WHO as the first-line treatment for malaria in 2006, and has since
been used to treat both mild and severe Plasmodium falciparum
malaria worldwide. As a result, ACT, along with scaled up preventative
measures in malaria endemic areas, has been responsible for significant
reductions in malaria-related mortality of more than 25% globally over the
past decade. The continued success of artemisinin as the gold-standard
antimalarial has been a major public health priority for local
governments, the WHO, and MORU for the past two decades. But while MORU
researchers were collating data for a longitudinal study on the resistance
profile of artemisinin on the northwestern border of Thailand, concerns
regarding tolerance to artemisinin in western Cambodia began to emerge1.
These concerns were confirmed in a 2008 study2, which reported
artemisinin resistance in approximately 3% of patients in the Battambang
Province2.

Responding quickly, University of Oxford researchers at MORU performed
two randomised trials comparing the effectiveness of artemisinin-based
treatments for uncomplicated falciparum malaria in western Cambodia and
northwestern Thailand3. Published in June 2009, this study
showed reduced in vivo susceptibility to artesunate in Plasmodium
falciparum parasites in western Cambodia, resulting in a resistance
rate of approximately 30% - ten times higher than previous reports3.
One month later, in July 2009 the MORU published a study showing that
standard dosing of artemisinin can cause resistance in patients with low
drug levels and high parasite burdens, particularly among children and
pregnant women. This study also showed that patients with
hyperparasitaemia (a parasite blood count greater than 250,000 per µL),
who had received several treatments, were at a greater risk of
reoccurrence and resistance to artemisinin therapy. This research
emphasised the importance of ensuring that only artemisinin combinations
are used, rather than monotherapies. It also highlighted the importance of
tailoring treatment regimens to suit the pharmacokinetic needs of
patients, particularly children, pregnant women, and those suffering from
hyperparasitaemia4.

A 2010 review from MORU summarised the extent of artemisinin resistance
and outlined key strategies to delay and contain its spread, including5:
increased coverage with prompt and effective antimalarial treatment;
reduction of drug pressure, e.g. exploring alternative treatments; mass
ACT administration to targeted populations; increased surveillance,
investigation, and targeted control measures; further research into
identifying multiple first-line therapies; and further research into
alternative control methods, e.g. malaria vaccines5.

In 2012 MORU published its ten-year longitudinal study on the resistance
profile of artemisinin therapy on the northwestern border of Thailand,
between 2001 and 2010. This pivotal study not only showed that
artemisinin-resistant Plasmodium falciparum parasites had emerged
along the Thailand-Myanmar border, eight years prior to publication, it
also reported that rates of resistance were rapidly increasing6,
further emphasising the need for rapid containment.

References to the research

1. Jambou, R. et al. Resistance of Plasmodium falciparum field
isolates to in-vitro artemether and point mutations of the SERCA-type
PfATPase6. Lancet366, 1960-1963 (2005). http://dx.doi.org/10.1016/S0140-6736(05)67787-2.
First study to raise concerns about tolerance to artemisinin in
western Cambodia.

6. Phyo, A. P. et al. Emergence of artemisinin-resistant malaria
on the western border of Thailand: a longitudinal study. Lancet379,
1960-1966 (2012). doi: 10.1111/j.1365-2125.2011.04103.x. Mahidol-Oxford's
ten-year longitudinal study showing that artemisinin-resistant
Plasmodium falciparum parasites had emerged along the Thailand-Myanmar
border eight years prior to publication, and that rates of resistance
were rapidly increasing.

This research was funded by the Wellcome Trust.

Details of the impact

Researchers from the University of Oxford's Mahidol-Oxford Research Unit,
Thailand (MORU), were the first to expose the full extent of artemisinin
resistance in western Cambodia, prompting urgent action from local
governments and the WHO7. The Unit's longitudinal study showing
the spread of resistance to the Thailand-Myanmar border confirmed the
ferociousness of the problem, prompting further action and funding from
health authorities and governments around the world for rapid research and
containment programmes. Following the publication of MORU's June 20093
paper on artemisinin resistance in western Cambodia the WHO released a Global
report on antimalarial drug efficacy and drug resistance: 2000-20108,
which cites MORU's 2009 study as key evidence to artemisinin resistance.
This research also provided evidence for the WHO's definition of
resistance, characterised by slow rates of parasite clearance8.

MORU's July 20094 paper also provided evidence to the WHO that
measures can be taken in the clinic to prevent the spread of resistance8.
The study was cited in the WHO's Global report on antimalarial drug
efficacy and drug resistance: 2000-20108, which
emphasised the need for correct prescribing, adherence to prescribed drug
regimens, and provision of effective treatment regimens, particularly
among hyperparasitaemic patients. In 2011 the WHO released its Global
plan for artemisinin resistance containment (GPARC)9 - a
worldwide "call to action" for the prevention of further resistance. The
GPARC report cites evidence from MORU4 studies and recommends
several courses of action, reflecting MORU's key strategies5
for the containment of malaria resistance, including9:

As a result of the University of Oxford's research and the subsequent
call to action from the WHO, a number of government organisations have
pledged assistance for further research into artemisinin resistance in
Southeast Asia. The UK Department for International Development has set up
the Artemisinin Resistant Malaria Program appointing MORU as the
lead research institute on the project. The aim of this collaborative
program is to rapidly identify and geographically contain artemisinin
resistance, in order to prevent its spread to other parts of Southeast
Asia and Africa10. As part of this program the Tracking
Resistance to Artemisinin Collaboration was launched in January
2011, to investigate the spread of parasite resistance to
artemisinin-based therapies in western Cambodia, and on the Thailand
Myanmar border11. MORU's 2012 study, which emphasised the
global threat of artemisinin resistance, has received worldwide media
attention from Reuters12 and TIME magazine13, to The
Times of India14, and the Deccan Herald (India)15.
Such widespread media attention has highlighted the problem of resistance,
encouraging charities and investors to support global containment
programs. This media attention has also improved social understanding of
the problem in high-risk areas, such as India.

Increased funding for research into artemisinin resistance has led to
ground-breaking outcomes in the genetic understanding of malaria
parasites. A recent discovery from Oxford University researchers,
published in April 2013, shows that malaria parasites in western Cambodia
are genetically different from the strains of parasites found in other
parts of the world, such as Africa. These findings will make it possible
for health care workers to track the resistant strains of malaria
parasites as they emerge, and to develop an appropriate response16.

Sources to corroborate the impact

Samarasekera, U. Countries race to contain resistance to key
antimalarial. Lancet374, 277-280 (2009). http://dx.doi.org/10.1016/S0140-6736(09)61349-0.
Review by Udani Samarasekera, senior editor of The Lancet,
regarding the emergence of artemisinin resistance. This review
outlines the timeline of the discovery of resistance, showing the
pivotal role of Mahidol-Oxford's research in identifying resistance,
and prompting action from local governments and the WHO.

World Health Organization. Global Report on Antimalarial Drug
Efficacy and Drug Resistance: 2000-2010. Geneva:WHO (2010).
[Accessed June 2013]http://whqlibdoc.who.int/publications/2010/9789241500470_eng.pdfWHO report released in 2010 following Mahidol-Oxford's
identification of artemisinin resistance. This report directly cites
Mahidol-Oxford's June 2009 study as key evidence for artemisinin
resistance, and its July 2009 study as evidence for the use of
combination therapy over monotherapy, for the prevention of
resistance.

World Health Oganisation. Global Plan For Artemisinin Resistance
Containment (GPARC). Geneva: WHO, (2011). [Accessed July 2013]http://www.who.int/malaria/publications/atoz/artemisinin_resistance_containment_201
1.pdfWHO's Global plan for artemisinin resistance
containment, a worldwide "call to action" for the prevention of
further resistance, citing evidence from Mahidol-Oxford, and
recommending several courses of action, reflecting Mahidol-Oxford's
key strategies for the containment of malaria resistance.

Department for International Development - Research for Development
Project Record. Artemisinin Resistant Malaria Programme,
2010-2014.
[Accessed July 2013] http://r4d.dfid.gov.uk/Project/60881/Default.aspx.
Mahidol-Oxford is the lead research institute working on the UK
Department for International Development's, Artemisinin Resistant
Malaria Program.

Miotto, O. et al. Multiple populations of
artemisinin-resistant Plasmodium falciparum in Cambodia. Nat Genet.
45(6):648-55 (2013). doi: 10.1038/ng.2624. The most recent
discovery from Mahidol-Oxford shows that malaria parasites in
western Cambodia are genetically different from the strains of
parasites found in other parts of the world, such as Africa. This
will enable researchers to track resistant strains of malaria
parasites, allowing rapid detection of resistance as it emerges.